The long term goal of this project is to prevent HIV transmission. Using the drug delivery platform we developed for the ganciclovir intraocular implant, Vitrasert(R), we propose to develop an intravaginal ring microbicide formulation releasing the antiretroviral agents tenofovir DF, emtricitabine and maraviroc. This drug combination has been chosen for potency, synergistic action, and the prevention of resistance. The rationale for the choice of tenofovir DF and emtricitabine is very strong as these are currently the only drugs to have demonstrated efficacy in clinical studies of HIV transmission. Maraviroc the only other antiretroviral to show protection against SHIV transmission in macaques. Funded in part by R21, R33, and SBIR grants from the NIAID, we have successfully adapted the Vitrasert(R) platform and safely delivered multiple antiretrovirals in multiple animal models. An Investigational New Drug Exemption from the FDA, no 114173 has been allowed pending the resolution of two clinical hold items comprising manufacturing specifications and animal toxicity testing. The specific aims of the Phase 1 portion of this proposal are to resolve these hold issues. The development of an effective microbicide IVR could save millions of lives per year and is therefore highly significant. As the developers of the only FDA approved antiviral delivery device we believe we are uniquely qualified to develop such a product. We believe our IVRs demonstrate dramatic improvement over the current state of the art. We can deliver drugs of high and low aqueous solubility simultaneously, with control of release rate over a wide range. The team of investigators is expert in chemistry, pharmacokinetics, engineering, gynecological clinical trials and drug development, and we have experience in all aspects of the drug development process, from concept to approval and marketing. The milestone defining successful completion of this work will be the granting of IND No 114173 to enable Phase I clinical studies.